rs1060500653

Positions:

• chr2-144390000-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014795.4(ZEB2):​c.3095del​(p.Cys1032LeufsTer43) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZEB2 NM_014795.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.91

Genes affected

ZEB2 (HGNC:14881): (zinc finger E-box binding homeobox 2) The protein encoded by this gene is a member of the Zfh1 family of 2-handed zinc finger/homeodomain proteins. It is located in the nucleus and functions as a DNA-binding transcriptional repressor that interacts with activated SMADs. Mutations in this gene are associated with Hirschsprung disease/Mowat-Wilson syndrome. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 39 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-144390000-AC-A is Pathogenic according to our data. Variant chr2-144390000-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 405331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZEB2	NM_014795.4	c.3095del	p.Cys1032LeufsTer43	frameshift_variant	10/10	ENST00000627532.3
ZEB2	NM_001171653.2	c.3023del	p.Cys1008LeufsTer43	frameshift_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZEB2	ENST00000627532.3	c.3095del	p.Cys1032LeufsTer43	frameshift_variant	10/10	1	NM_014795.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mowat-Wilson syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 16, 2020	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the ZEB2 protein. Other variant(s) that disrupt this region (p.Arg1047Serfs*32, also known as H1049fsX1080) have been determined to be pathogenic (PMID: 16053902, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with ZEB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 405331). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys1032Leufs*43) in the ZEB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acid(s) of the ZEB2 protein. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The heterozygous p.Cys1032LeufsTer43 variant in ZEB2 was identified by our study in one individual with partial agenesis of the corpus callosum, polymicrogyria, and seizure. Trio exome analysis showed this variant to be de novo. The p.Cys1032LeufsTer43 variant in ZEB2 has not been previously reported in the literature in individuals with Mowat Wilson syndrome. This variant has also been reported in ClinVar (Variation ID: 405331) and has been interpreted as pathogenic by Invitae. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1032 and leads to a premature termination codon 43 amino acids downstream. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Heterozygous loss of function of the ZEB2 gene is an established disease mechanism in autosomal dominant Mowat Wilson syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for Mowat Wilson syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PS2_Supporting, PM2_Supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060500653; hg19: chr2-145147567;